Activation of the RET tyrosine kinase is involved in approximately 50% of cases of medullary thyroid carcinoma (MTC) and 20-25% of cases of papillary thyroid carcinoma (PTC). For medullary thyroid carcinoma, there is no effective therapy other than surgery. In this proposal, we will develop therapeutic approaches for MTC and PTC, based on inhibition of RET. We have shown that the indolecarbazole compunds of CEP-701 and CEP-751 inhibit RET and induce apoptosis in MTC cells in culture. Focusing mainly on MTC, this proposal will develop this observation, toward effective therapy for these diseases in humans. The effect of CEP-701 and CEP-751 on inhibition of RET activity and MTC growth will be evaluated in an animal model of human MTC. Combination therapy, using CEP-701 or DEP-751 and a conventional cytotoxic agent, will be examined. A library of tyrosine kinase inhibitors, structurally similar to CEP-701 and CEP-751, will be screened for more effective RET inhibitors. Correlative markers will be identified for RET inhibition, based on downstream effectors of RET signal transduction pathways. Immunological assays for these markers will be developed for future use in assessing the efficacy of RET inhibition in clinical settings. The effect of RET inhibition by CEP-701, CEP-751, or other compounds on several forms of RET commonly activated in MTC and PTC will be examined. In addition, the effect of RET inhibition therapy will be examined in tumors arising in the natural thyroid setting, in transgenic models of MTC and PTC.